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Objectives The purpose of our study was to describe children with life-threatening bleeding. Design We conducted a prospective observational study of children with life-threatening bleeding events. Setting Twenty-four childrens hospitals in the United States, Canada, and Italy participated. Subjects Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. Interventions Children were compared according bleeding etiology: trauma, operative, or medical. Measurements and main results Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. Conclusions Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.MethodsWe performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects’ clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.ResultWe observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.ConclusionsWe successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals’ genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

This study evaluates the impact of a 6-month care management intervention for 206 children diagnosed with comorbid attention deficit hyperactivity disorder (ADHD) from a sample of 321 five- to 12-year-old children recruited for treatment of behavior problems in 8 pediatric primary care offices. Practices were cluster-randomized to Doctor Office Collaboration Care (DOCC) or Enhanced Usual Care (EUC). Chart reviews documented higher rates of service delivery, prescription of medication for ADHD, and titration in DOCC (vs EUC). Based on complex conditional models, DOCC showed greater acute improvement in individualized ADHD treatment goals and follow-up improvements in quality of life and ADHD and oppositional defiant disorder goals. Medication use had a significant effect on acute and follow-up ADHD symptom reduction and quality of life. Medication continuity was associated with some long-term gains. A collaborative care intervention for behavior problems that incorporated treatment guidelines for ADHD in primary care was more effective than psychoeducation and facilitated referral to community treatment.

Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol.To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP).In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021.Boluses of HTS and mannitol were administered.Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments.A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted β, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted β, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (20 mm Hg: unadjusted β, -2.51; 95% CI, -3.86 to -1.15, P .001;25 mm Hg: unadjusted β, -3.88; 95% CI, -5.69 to -2.06, P .001;30 mm Hg: unadjusted β, -4.07; 95% CI, -6.35 to -1.79, P .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis.In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.

To assess the impact of plasma and platelet ratios and deficits in injured children with life-threatening bleeding.Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events.Twenty-four childrens hospitals in the United States, Canada, and Italy.Injured children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under activation of massive transfusion protocol.Weight-adjusted blood product volumes received during the bleeding event were recorded. Plasma:RBC ratio (plasma/RBC weight-adjusted volume in mL/kg) and platelet:RBC ratio (platelet/RBC weight-adjusted volume in mL/kg) were analyzed. Plasma deficit was calculated as RBC mL/kg - plasma mL/kg; platelet deficit was calculated as RBC mL/kg - platelet mL/kg.Of 191 patients analyzed, median (interquartile range) age was 10 years (5-15 yr), 61% were male, 61% blunt mechanism, and median (interquartile range) Injury Severity Score was 29 (24-38). After adjusting for Pediatric Risk of Mortality score, cardiac arrest, use of vasoactive medications, and blunt mechanism, a high plasma:RBC ratio (1:2) was associated with improved 6-hour survival compared with a low plasma:RBC ratio (odds ratio [95% CI] = 0.12 [0.03-0.52]; p = 0.004). Platelet:RBC ratio was not associated with survival. After adjusting for age, Pediatric Risk of Mortality score, cardiac arrest, and mechanism of injury, 6-hour and 24-hour mortality were increased in children with greater plasma deficits (10% and 20% increased odds of mortality for every 10 mL/kg plasma deficit at 6 hr [p = 0.04] and 24 hr [p = 0.01], respectively); 24-hour mortality was increased in children with greater platelet deficits (10% increased odds of 24-hr mortality for every 10 mL/kg platelet deficit [p = 0.02)]).In injured children, balanced resuscitation may improve early survival according to this hypothesis generating study. Multicenter clinical trials are needed to assess whether clinicians should target ratios and deficits as optimal pediatric hemostatic resuscitation practice.

Background Low-titer group O whole-blood (LTOWB) is being used for children with life-threatening traumatic bleeding. A survey was conducted to determine current LTOWB utilization and interest in participation in a randomized control trial (RCT) of LTOWB versus standard blood component transfusion in this population. Study design and methods Transfusion medicine (TM) directors and pediatric trauma directors at 36 US children's hospitals were surveyed by e-mail in June 2020. Hospitals were selected by participation in the Massive Transfusion Epidemiology and Outcomes in Children Study or being among the largest 30 children's hospitals by bed capacity per the Becker Hospital Review. Results The response rate was 83.3% (30/36) from TM directors and 88.9% (32/36) from trauma directors. The median of massive transfusion protocol activations for traumatic bleeding was reported as 12 (IQR 5.8-20) per year by TM directors. LTOWB was used by 18.8% (6/32) of trauma directors. Survey responses indicate that 86.7% (26/30) of TM directors and 90.6% (29/32) of trauma directors either moderately or strongly agree that a LTOWB RCT is important to perform. About 83.3% (25/30) of TM directors and 93.8% (30/32) of trauma directors were willing to participate in the proposed trial. About 80% (24/30) of TM directors and 71.9% (23/32) of trauma directors would transfuse RhD+ LTOWB to male children, but fewer would transfuse Rh + LTOWB to females [20% (6/30) TM directors and 37.5% (12/32) of trauma directors]. Conclusions A majority of respondents supported an RCT comparing LTOWB to component therapy in children with severe traumatic bleeding.

BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of two common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus (Der p), and IgE to Blattella germanica (Bla g) were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma study (VDKA), a multicenter, double-blind, randomized placebo-controlled trial of vitamin D(3) supplementation (4,000 IU/day) to prevent severe exacerbations in children with persistent asthma and vitamin D levels

Sulfonylurea receptor-1 (SUR1) is recognized increasingly as a key contributor to cerebral edema, hemorrhage progression, and possibly neuronal death in multiple forms of acute brain injury. SUR1 inhibition may be protective and is actively undergoing evaluation in Phase-2/3 trials of traumatic brain injury (TBI) and stroke. In adult TBI, SUR1 expression is associated with intracranial hypertension and contusion expansion; its role in pediatric TBI remains unexplored. We tested 61 cerebrospinal fluid (CSF) samples from 16 pediatric patients with severe TBI enrolled in the multicenter Phase-3 randomized controlled “Cool Kids” trial and seven non-brain injured pediatric controls for SUR1 expression by enzyme-linked immunosorbent assay. Linear mixed models evaluated associations between mean SUR1 and intracranial pressure (ICP) over the first seven days and pediatric Glasgow Outcome Scale-Extended (GOS-E Peds) over the initial year after injury. SUR1 was undetectable in control CSF and increased versus control in nine of 16 patients with TBI. Mean SUR1 was not associated with age, sex, or therapeutic hypothermia. Each 1-point increase in initial Glasgow Coma Score was associated with a 1.68 ng/mL decrease in CSF SUR1. The CSF SUR1 was associated with increased ICP over seven days (b = 0.73, p = 0.004) and worse (higher) GOS-E Peds score (b = 0.24, p = 0.004). In this exploratory pediatric study, CSF SUR1 was undetectable in controls and variably elevated in severe TBI. Mean CSF SUR1 concentration was associated with ICP and outcome. These findings are distinct from our previous report in adults with severe TBI, where SUR1 was detected universally. SUR1 may be a viable therapeutic target in a subset of pediatric TBI, and further study is warranted.

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight

Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies.To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI.This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022.Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group).The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion.A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P .001).In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Introduction: There is growing evidence that computer-delivered or computer-assisted forms of cognitive behavior therapy (CCBT) are helpful, but cost-effectiveness versus standard therapies is not well established. Objective: To evaluate the cost-effectiveness of a therapist-supported method for CCBT in comparison to standard cognitive behavior therapy (CBT). Methods: A total of 154 drug-free major depressive disorder outpatients were randomly assigned to either 16 weeks of standard CBT (up to twenty 50-min sessions) or CCBT using the Good Days Ahead program (including up to 5.5 h of therapist contact). Outcomes were assessed at baseline, weeks 8 and 16, and at 3 and 6 months post-treatment. Economic analyses took into account the costs of services received and work/social role impairment. Results: In the context of almost identical efficacy, a form of CCBT that used only about one third the amount of therapist contact as conventional CBT was highly cost-effective compared to conventional therapy and reduced the adjusted cost of treatment by USD 945 per patient. Conclusions: A method of CCBT that blended internet-delivered modules and abbreviated therapeutic contact reduced the cost of treatment substantially without adversely affecting outcomes. Results suggest that use of this approach can more than double the access to CBT. Because clinician support in CCBT can be provided by telephone, videoconference, and/or email, this highly efficient form of treatment could be a major advance in remote treatment delivery.

The relationship between perceived neighborhood contentedness and physical activity was evaluated in the Add Health study population. Wave I includes 20,745 respondents (collected between 1994 and 1995) and wave II includes 14,738 (71 %) of these same students (collected in 1996). Multinomial logistic regression was used to evaluate this relationship in both wave I and wave II of the sample. Higher levels of Perceived Neighborhood Contentedness were associated with higher reports of physical activity in both males and females and in both waves. For every one-point increment in PNS, males were 1.3 times as likely to report being highly physically active than low (95 % CI 1.23–1.37) in wave 1 and 1.25 times as likely in wave 2 (95 % CI 1.17–1.33). Females were 1.17 (95 % CI 1.12–1.22) times as likely to report being highly active than low and 1.22 times as likely in wave 2 (95 % CI 1.17–1.27) with every one-point increment. PNC appears to be significantly associated with physical activity in adolescents. Involving the community in the development of intervention programs could help to raise the contentedness of adolescents in these communities.

Context.—Jejunoileal neuroendocrine tumors (JINETs) are slow-growing, malignant tumors that are often associated with protracted survival, despite their frequent presentation at an advanced stage. A subset of JINETs is complicated by intestinal ischemic necrosis (IIN), which leads to their initial clinical presentation. Objective.—To assess the effect of IIN on overall survival in patients with JINETs. Design.—Ten JINETs with IIN during a 14-year period and a control group of 52 JINETs without IIN were identified retrospectively. The hematoxylin-eosin slides and gross descriptions were reviewed, and pathologic features were assessed. Overall survival was compared between the 2 groups using the Kaplan Meier method and Cox proportional hazards model. Results.—At 1 year postresection, only 40% (4 of 10) of the patients with IIN were alive, whereas 94% (49 of 52) of those without IIN were alive (P < .001). Patients with IIN were significantly older than those without IIN (median, 83 years versus 65.5 years, P = .001). By univariate Cox proportional hazards regression, IIN was associated with a 4.30-fold increased risk of death (95% confidence interval 1.75–10.56; P = .001). When controlling for age, advanced stage (stage III or IV), tumor grade, and synchronous carcinoma in a multivariate analysis, IIN showed a trend toward prognostic significance (2.31-fold increased risk of death; 95% confidence interval, 0.85–6.27; P = .10). Conclusions.—The pathologic identification of tumor-associated IIN portends a worse overall survival among patients with JINETs.

The Partnerships for Families project is a randomized clinical trial to evaluate the effectiveness of Alternatives for Families: A Cognitive Behavioral Therapy (AF-CBT), an evidence-based treatment (EBT) for families who are at risk of or have histories of child physical abuse. Across 10 agencies whose programs were supported by referrals from the mental health or child welfare system, individual providers were randomized to receive AF-CBT training ( n = 90) in a 6-month learning community or treatment as usual (TAU; n = 92) which provided trainings per agency routine. We recruited families served by providers in the AF-CBT ( n = 122) and TAU ( n = 73) conditions and collected multiple outcomes at up to four time points (0, 6, 12, and 18 months). Using univariate tests and growth curve models, the analyses revealed that AF-CBT (vs. TAU) showed improvements in both service systems (e.g., abuse risk, family dysfunction) or one service system (e.g., threats of force, child to parent minor assault), with some outcomes showing no improvement (e.g., parental anger). These findings are discussed in relation to AF-CBT, service system, provider, and family characteristics, and training/dissemination methods that affect the delivery of an EBT for this population in community settings.

Objective The aims of this study were to assess the agreement of physicians and nurses performing tender and swollen joint counts (TJCs/SJCs) in rheumatoid arthritis (RA) and identify factors that might influence their examinations including patient age, sex, race, RA disease duration, body mass index, RA disease activity level, comorbid fibromyalgia, comorbid osteoarthritis, and levels of acute-phase reactants. Methods Seventy-two RA participants underwent TJCs/SJCs of 28 joints using a standardized protocol by 2 nurses and 2 rheumatologists. Demographic, laboratory, radiographic, and clinical data were obtained to assess the influence of these factors on TJCs/SJCs. Intraclass correlations (ICCs) among examiners were determined for TJCs/SJCs. Nurse-physician differences and agreement of individual joints were evaluated using Cohen κ. Analysis of variance was performed to detect differences in means between examiners for TJCs/SJCs. Intraclass correlation and Fisher Z tests were used to identify factors influencing TJCs/SJCs. Results Agreement was strong among these nurses and physicians for total TJCs/SJCs (ICC = 0.84/ICC = 0.79, respectively). κ was best for hand joint tenderness and poorest for shoulder swelling. Some significant differences in mean TJCs/SJCs were found between examiners. Fibromyalgia significantly reduced agreement of both TJCs and SJCs. Agreement of TJC was significantly reduced when patients had lower disease activity, greater work impairment, lower mental health quality of life, and elevated erythrocyte sedimentation rate, whereas female sex, assessor's perception of but not radiographic hand osteoarthritis, and elevated C-reactive protein significantly reduced agreement for SJC. Conclusions Strong agreement was found among nurses and physicians for total 28-joint counts, with agreement at individual joints being stronger for tenderness than swelling. Fibromyalgia significantly reduced ICCs of TJCs/SJCs.

Objectives Conclusive evidence is lacking regarding the benefits and risks of performing off-pump versus on-pump coronary artery bypass graft (CABG) for patients with diabetes. This study aims to compare clinical outcomes after off-pump and on-pump procedures for patients with diabetes. Methods The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled patients with type 2 diabetes and documented coronary artery disease, 615 of whom underwent CABG during the trial. The procedural complications, 30-day outcomes, long-term clinical and functional outcomes were compared between the off-pump and on-pump groups overall and within a subset of patients matched on propensity score. Results On-pump CABG was performed in 444 (72%) patients, and off-pump CABG in 171 (28%). The unadjusted 30-day rate of death/myocardial infarction (MI)/stroke was significantly higher after off-pump CABG (7.0 vs 2.9%, P = 0.02) despite fewer complications (10.3 vs 20.7%, P = 0.003). The long-term risk of death [adjusted hazard ratio (aHR): 1.41, P = 0.2197] and major cardiovascular events (death, MI or stroke) (aHR: 1.47, P = 0.1061) did not differ statistically between the off-pump and on-pump patients. Within the propensity-matched sample (153 pairs), patients who underwent off-pump CABG had a higher risk of the composite outcome of death, MI or stroke (aHR: 1.83, P = 0.046); the rates of procedural complications and death did not differ significantly, and there were no significant differences in the functional outcomes. Conclusions Patients with diabetes had greater risk of major cardiovascular events long-term after off-pump CABG than after on-pump CABG.

Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score ≤ 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (

OBJECTIVES To understand the relationship between the timing of initiation of nutritional support in children with severe traumatic brain injury and outcomes. DESIGN Secondary analysis of a randomized, controlled trial of therapeutic hypothermia (Pediatric Traumatic Brain Injury Consortium: Hypothermia, also known as "the Cool Kids Trial" (NCT 00222742). SETTINGS Fifteen clinical sites in the United States, Australia, and New Zealand. SUBJECTS Inclusion criteria included 1) age less than 18 years, 2) postresuscitation Glasgow Coma Scale less than or equal to 8, 3) Glasgow Coma Scale motor score less than 6, and 4) available to be randomized within 6 hours after injury. Exclusion criteria included normal head CT, Glasgow Coma Scale equals to 3, hypotension for greater than 10 minutes ( 30 min), pregnancy, penetrating injury, and unavailability of a parent or guardian to consent at centers without emergency waiver of consent. INTERVENTIONS Therapeutic hypothermia (32-33°C for 48 hr) followed by slow rewarming for the primary study. For this analysis, the only intervention was the extraction of data regarding nutritional support from the existing database. MEASUREMENTS AND MAIN RESULTS Timing of initiation of nutritional support was determined and patients stratified into four groups (group 1-no nutritional support over first 7 d; group 2-nutritional support initiated < 48 hr after injury; group 3-nutritional support initiated 48 to < 72 hr after injury; group 4-nutritional support initiated 72-168 hr after injury). Outcomes were also stratified (mortality and Glasgow Outcomes Scale-Extended for Pediatrics; 1-4, 5-7, 8) at 6 and 12 months. Mixed-effects models were performed to define the relationship between nutrition and outcome. Children (n = 90, 77 randomized, 13 run-in) were enrolled (mean Glasgow Coma Scale = 5.8); the mortality rate was 13.3%. 57.8% of subjects received hypothermia Initiation of nutrition before 72 hours was associated with survival (p = 0.01), favorable 6 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.03), and favorable 12 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.04). Specifically, groups 2 and 3 had favorable outcomes versus group 1. CONCLUSIONS Initiation of nutritional support before 72 hours after traumatic brain injury was associated with decreased mortality and favorable outcome in this secondary analysis. Although this provides a rationale to initiate nutritional support early after traumatic brain injury, definitive studies that control for important covariates (severity of injury, clinical site, calories delivered, parenteral/enteral routes, and other factors) are needed to provide definitive evidence on the optimization of the timing of nutritional support after severe traumatic brain injury in children.

Background & Aims Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain. We investigated whether abdominal imaging features accurately predict patterns of pain. Methods We collected data from participants in the North American Pancreatitis Study 2 Continuation and Validation, a prospective multicenter study of patients with chronic pancreatitis performed at 13 expert centers in the United States from July 2008 through March 2012. Chronic pancreatitis was defined based on the detection of characteristic changes by cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, or histology analyses. Patients were asked by a physician or trained clinical research coordinator if they had any abdominal pain during the year before enrollment, those who responded "yes" were asked to select from a list of 5 pain patterns. By using these patterns, we classified patients' pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms. Results Data were collected from 518 patients (mean age, 52 ± 14.6 y; 55% male; and 87.6% white). The most common physician-identified etiologies were alcohol (45.8%) and idiopathic (24.3%); 15.6% of patients reported no abdominal pain in the year before enrollment. The most common individual pain pattern was described as constant mild pain with episodes of severe pain and was reported in 45% of patients. The most common imaging findings included pancreatic ductal dilatation (68%), atrophy (57%), and calcifications (55%). Imaging findings were categorized as obstructive for 20% and as inflammatory for 25% of cases. The distribution of individual imaging findings was similar among patients with different patterns of pain. The distribution of pain patterns did not differ among clinically relevant groups of imaging findings. Conclusions Mechanisms that determine patterns and severity of pain in patients with chronic pancreatitis are largely independent of structural variants observed by abdominal imaging techniques. Pancreas-relevant quantitative and qualitative pain measures should be included in the evaluation of patients with chronic pancreatitis to assess pain severity independently of imaging findings.

The authors evaluated the efficacy and durability of a therapist-supported method for computer-assisted cognitive-behavioral therapy (CCBT) in comparison to standard cognitive-behavioral therapy (CBT).A total of 154 medication-free patients with major depressive disorder seeking treatment at two university clinics were randomly assigned to either 16 weeks of standard CBT (up to 20 sessions of 50 minutes each) or CCBT using the "Good Days Ahead" program. The amount of therapist time in CCBT was planned to be about one-third that in CBT. Outcomes were assessed by independent raters and self-report at baseline, at weeks 8 and 16, and at posttreatment months 3 and 6. The primary test of efficacy was noninferiority on the Hamilton Depression Rating Scale at week 16.Approximately 80% of the participants completed the 16-week protocol (79% in the CBT group and 82% in the CCBT group). CCBT met a priori criteria for noninferiority to conventional CBT at week 16. The groups did not differ significantly on any measure of psychopathology. Remission rates were similar for the two groups (intent-to-treat rates, 41.6% for the CBT group and 42.9% for the CCBT group). Both groups maintained improvements throughout the follow-up.The study findings indicate that a method of CCBT that blends Internet-delivered skill-building modules with about 5 hours of therapeutic contact was noninferior to a conventional course of CBT that provided over 8 additional hours of therapist contact. Future studies should focus on dissemination and optimizing therapist support methods to maximize the public health significance of CCBT.

OBJECTIVE: To characterize racial/ethnic and insurance disparities in the utilization of health care services among US adults with traumatic brain injury (TBI). METHODS: The PubMed database was used to search for articles that directly examined the association between race/ethnicity or insurance disparities and health care utilization among patients with TBI. Eleven articles that met the criteria and were published between June 2011 and June 2016 were finally included in the review. RESULTS: Lack of insurance was significantly associated with decreased use of in-hospital and post-hospital health care services among patients with TBI. However, mixed results were reported for the associations between insurance types and health care utilization. The majority of studies reported that racial/ethnic minorities were less likely to use in-hospital and post-hospital health care services, while some studies did not indicate any significant relation between race/ethnicity and health care utilization among patients with TBI. CONCLUSIONS: This review provides evidence of a relation between insurance status and health care utilization among US adults with TBI. Insurance status may also account for some portion of the relation between race/ethnicity and health care utilization.

Small series have suggested that outcomes after abusive head trauma are less favorable than after other injury mechanisms. We sought to determine the impact of abusive head trauma on mortality and identify factors that differentiate children with abusive head trauma from those with traumatic brain injury from other mechanisms.First 200 subjects from the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial-a comparative effectiveness study using an observational, cohort study design.PICUs in tertiary children's hospitals in United States and abroad.Consecutive children (age18 yr) with severe traumatic brain injury (Glasgow Coma Scale ≤ 8; intracranial pressure monitoring).None.Demographics, injury-related scores, prehospital, and resuscitation events were analyzed. Children were dichotomized based on likelihood of abusive head trauma. A total of 190 children were included (n = 35 with abusive head trauma). Abusive head trauma subjects were younger (1.87 ± 0.32 vs 9.23 ± 0.39 yr; p0.001) and a greater proportion were female (54.3% vs 34.8%; p = 0.032). Abusive head trauma were more likely to 1) be transported from home (60.0% vs 33.5%; p0.001), 2) have apnea (34.3% vs 12.3%; p = 0.002), and 3) have seizures (28.6% vs 7.7%; p0.001) during prehospital care. Abusive head trauma had a higher prevalence of seizures during resuscitation (31.4 vs 9.7%; p = 0.002). After adjusting for covariates, there was no difference in mortality (abusive head trauma, 25.7% vs nonabusive head trauma, 18.7%; hazard ratio, 1.758; p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (abusive head trauma, 66.7% vs nonabusive head trauma, 69.0%).In this large, multicenter series, children with abusive head trauma had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other traumatic brain injury populations in children, female predominance was seen in abusive head trauma in our cohort. Similar mortality rates and refractory intracranial pressure deaths suggest that children with severe abusive head trauma may benefit from therapies including invasive monitoring and adherence to evidence-based guidelines.

Our aim was to validate recent epidemiologic trends and describe the distribution of TIGAR-O risk factors in chronic pancreatitis (CP) patients. The NAPS-2 Continuation and Validation (NAPS2-CV) study prospectively enrolled 521 CP patients from 13 US centers from 2008 to 2012. CP was defined by definitive changes in imaging, endoscopy, or histology. Data were analyzed after stratification by demographic factors, physician-defined etiology, participating center, and TIGAR-O risk factors. Demographics and physician-defined etiology in the NAPS2-CV study were similar to the original NAPS2 study. Mean age was 53 years (IQR 43, 62) with 55% males and 87% white. Overall, alcohol was the single most common etiology (46%) followed by idiopathic etiology (24%). Alcohol etiology was significantly more common in males, middle-aged (35–65 years), and non-whites. Females and elderly (≥65 years) were more likely to have idiopathic etiology, while younger patients (

To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy.Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (≤14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16; scored 0-3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue).Http://clinicaltrials.gov, NCT00021528.Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression ≤7 or QIDS-SR16 ≤5); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS).At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment-emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P 0.0001), and reduced mental and physical function at outcome (P ≤ 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P 0.0001), indicative of more severe functional impairment.Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post-hoc analysis design.

Background Respiratory tract infections are a major cause of outpatient visits, yet only a portion is tested to determine the etiologic organism. Multiplex reverse transcriptase polymerase chain reaction (MRT-PCR) assays for detection of multiple viruses are being used increasingly in clinical settings. Methods During January–April 2012, outpatients with acute respiratory illness (≤7 days) were tested for influenza using singleplex RT-PCR (SRT-PCR). A subset was assayed for 18 viruses using MRT-PCR to compare detection of influenza and examine the distribution of viruses and characteristics of patients using multinomial logistic regression. Results Among 662 participants (6 months–82 years), detection of influenza was similar between the MRT-PCR and SRT-PCR (κ = 0·83). No virus was identified in 267 (40.3%) samples. Commonly detected viruses were human rhinovirus (HRV, 15·4%), coronavirus (CoV, 10·4%), respiratory syncytial virus (RSV, 8·4%), human metapneumovirus (hMPV, 8·3%), and influenza (6%). Co-detections were infrequent (6·9%) and most commonly occurred among those

We analyzed the public STAR*D database to better characterize the baseline clinical characteristics and functional outcomes of patients with major depressive disorder (MDD) who experienced partial response in order to better understand the burden associated with this outcome.Patients (n=2,876) received treatment with citalopram. The last available Quick Inventory of Depressive Symptoms (QIDS-SR) from the 12-week treatment period was used to assign subjects to one of three groups: remitters QIDS-SR≤5; non-responders QIDS-SR5 and25% reduction from baseline; and partial responders QIDS-SR5 and ≥25% reduction from baseline. Baseline sociodemographic and clinical characteristics were compared across groups, as well as functional outcomes at Level 1 exit. RESULTS. Of the 2,876 patients, 943 patients (33%) were classified as remitters, 1069 (37%) as partial responders, and 854 (30%) as non-responders. The groups differed on a number of pre-treatment course of illness variables and comorbidities. In addition, remitters, partial responders, and non-responders all separated on posttreatment quality of life and functional outcomes at Level 1 exit.Partial responders demonstrated significant functional impairment at Level 1 exit, differing significantly from the patients who remitted on quality of life, mental and physical functioning, and social and work-related impairment. Adjusted outcomes showed similar differences. Differences in baseline rates of suicidality, comorbidity, and atypical presentations of depression were also observed between outcome groups. Given the substantial clinical and economic burden associated with functional impairment in depression, the need to fully treat partially responding patients to achieve depression remission and restoration of functioning is highlighted by this work.

OBJECTIVE: To assess the efficacy of collaborative care for behavior problems, attention-deficit/hyperactivity disorder (ADHD), and anxiety in pediatric primary care (Doctor Office Collaborative Care; DOCC). METHODS: Children and their caregivers participated from 8 pediatric practices that were cluster randomized to DOCC (n = 160) or enhanced usual care (EUC; n = 161). In DOCC, a care manager delivered a personalized, evidence-based intervention. EUC patients received psychoeducation and a facilitated specialty care referral. Care processes measures were collected after the 6-month intervention period. Family outcome measures included the Vanderbilt ADHD Diagnostic Parent Rating Scale, Parenting Stress Index-Short Form, Individualized Goal Attainment Ratings, and Clinical Global Impression-Improvement Scale. Most measures were collected at baseline, and 6-, 12-, and 18-month assessments. Provider outcome measures examined perceived treatment change, efficacy, and obstacles, and practice climate. RESULTS: DOCC (versus EUC) was associated with higher rates of treatment initiation (99.4% vs 54.2%; P < .001) and completion (76.6% vs 11.6%, P < .001), improvement in behavior problems, hyperactivity, and internalizing problems (P < .05 to .01), and parental stress (P < .05–.001), remission in behavior and internalizing problems (P < .01, .05), goal improvement (P < .05 to .001), treatment response (P < .05), and consumer satisfaction (P < .05). DOCC pediatricians reported greater perceived practice change, efficacy, and skill use to treat ADHD (P < .05 to .01). CONCLUSIONS: Implementing a collaborative care intervention for behavior problems in community pediatric practices is feasible and broadly effective, supporting the utility of integrated behavioral health care services.

OBJECTIVE Obesity and major depressive disorder often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome are not well studied. METHODS Adults (n = 662) with major depressive disorder in the Combining Medications to Enhance Depression Outcomes study were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12-week primary treatment phase and 16-week follow-up. Body mass index (BMI) was calculated at baseline and categorized according to World Health Organization criteria: normal or low weight (NW), overweight, Obese I and Obese II+. A repeated-effects model, unadjusted and adjusted for baseline variables, assessed outcomes. RESULTS Obesity was common (46.2%), only 25.5% were NW. Higher BMI was associated with greater medical illness (p < .001), social phobia (p = .003), and bulimia (p = .026). Lower BMI was associated with more frequent post-traumatic stress disorder (p = .002) and drug abuse (p < .001). Treatment outcomes did not differ including Week 12 remission rates (NW 36%, overweight 40%, Obese I 43%, Obese II+ 37%; p = .69). Lower BMI was associated with more frequent (p = .024 [unadjusted] and .053 [adjusted]) and more severe (p = .008 [unadjusted] and .053 [adjusted]) adverse effects. CONCLUSIONS BMI was related to clinical presentation and prevalence of comorbidities, but not antidepressant outcomes. Lower BMI classes had more psychiatric comorbidities, potentially obscuring the relationship between BMI and antidepressant effects. Trial Registration ClinicalTrials.gov identifier: NCT00590863.

The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity.Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time.Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression.Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to persistent impairment in occupational productivity, implying a need for additional, possibly novel, treatments.

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.

Multiple treatment options are available for patients who do not respond to initial treatment for major depressive disorder. Previous results show that bupropion, sertraline, and venlafaxine are comparable in terms of therapeutic effectiveness following unsuccessful treatment with citalopram. In this study, we extended these results by incorporating costs of treatment to determine if one option was more cost-effective relative to others.In the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial, 727 patients were randomly assigned to a switch drug treatment during level 2; 239 (33%) were assigned to bupropion, 238 (33%) to sertraline, and 250 (34%) to venlafaxine. For each study medication, the total costs included the costs of the medication, other concomitant medication and antidepressants, and health care facility utilization. Effectiveness was measured as remission and response. Cost-effectiveness was assessed as net health benefits. Stochastic analysis was performed by using the bootstrapping method.During level 2, mean medication costs were significantly higher for venlafaxine than for bupropion and sertraline ($968, $607, and $703, respectively). There were no significant differences among the switch medications in costs for other medications and health care facility utilization. Although the total costs were significantly different for the three medications (p=.025), none of the pairwise differences between medications were significant. Also, after jointly estimating costs and effects, the analyses found that net health benefits were not significantly different among the three drugs.After unsuccessful treatment with citalopram, the switch options of bupropion, sertraline, and venlafaxine were not significantly different from each other in terms of cost-effectiveness.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

OBJECTIVE: In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. METHOD: For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. RESULTS: At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. CONCLUSIONS: While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.

OBJECTIVE: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is designed to evaluate the longitudinal outcome of patients with bipolar disorder. The STEP-BD disease-management model is built on evidence-based practices and a collaborative care approach designed to maximize specific and nonspecific treatment mechanisms. This prospective study examined the longitudinal relationships between patients' satisfaction with care, levels of hope, and life functioning in the first 1000 patients to enter STEP-BD. METHODS: The study used scores from the Care Satisfaction Questionnaire, Beck Hopelessness Scale, Range of Impaired Functioning Tool, Young Mania Rating Scale, and Montgomery-Asberg Depression Rating Scale at 5 time points during a 1-year interval. Analyses tested mediational pathways between care satisfaction, hope, and life functioning, depression, and mania using mixed-effects (random and fixed) regression models. RESULTS: Increases in care satisfaction were associated with decreased hopelessness (P < .01) but not related to symptoms of depression or mania. Similarly, decreased hopelessness was associated with better life functioning (P < .01) but not related to symptoms of depression or mania. Depression was independently associated with poorer life functioning (P < .0001). CONCLUSIONS: This study provided support for the hypothesized mediational pathway between care satisfaction, hopelessness, and life functioning. Findings suggest that providing care that maximizes patient hope may be important. By so doing, patients might overcome the learned helplessness/hopelessness that often accompanies a cyclical illness and build a realistic illness-management strategy.

We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230-11 874) to 1878 (653-7791) after therapy (p = 0.001) and to 1400 (850-8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714-14 405) to

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

Secondary insults such as hypotension or hemorrhagic shock (HS) can greatly worsen outcome after traumatic brain injury (TBI). We recently developed a mouse combined injury model of TBI and HS using a controlled cortical impact (CCI) model and showed that 90 minutes of HS can exacerbate neuronal death in hippocampus beneath the contusion. This combined injury model has three clinically relevant phases, a shock, pre hospital, and definitive care phases. Mice were randomly assigned to four groups, shams as well as a CCI only, an HS only, and a CCI + HS groups. The CCI and HS reduced cerebral blood flow (CBF) in multiple regions of interest (ROIs) in the hemisphere ipsilateral and contralateral to injury. Hemorrhagic shock to a level of ~30 mm Hg exacerbated the CCI-induced CBF reductions in multiple ROIs ipsilateral to injury (hemisphere and thalamus) and in the hemisphere contralateral to injury (hemisphere, thalamus, hippocampus, and cortex, all P < 0.05 versus CCI only, HS only or both). An important effect of HS duration was also seen after CCI with maximal CBF reduction seen at 90 minutes ( P < 0.0001 group-time effect in ipsilateral hippocampus). Given that neuronal death in hippocampus is exacerbated by 90 minutes of HS in this model, our data suggest an important role for exacerbation of posttraumatic ischemia in mediating the secondary injury in CCI plus HS. In conclusion, the serial, non invasive assessment of CBF using ASL-MRI (magnetic resonance imaging with arterial spin labeling) is feasible in mice even in the complex setting of combined CCI + HS. The impact of resuscitation therapies and various mutant mouse strains on CBF and other outcomes merits investigation in this model.

The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0–10) [N=81], moderate (11–15) [N=238], severe (16–20) [N=260] and very severe (21–27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severy group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/− 1.99 suicide attempts in the severe group versus o.o +/−0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbitities (e..g. [at p < 0.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9 % of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < 0.03) . These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.

The Partnerships for Families project is a randomized clinical trial designed to evaluate the implementation of Alternatives for Families: A Cognitive–Behavioral Therapy (AF-CBT), an evidence-based treatment for family conflict, coercion, and aggression, including child physical abuse. To evaluate the effectiveness of a training program in this model, 182 community practitioners from 10 agencies were randomized to receive AF-CBT training ( n = 90) using a learning community model (workshops, consultation visits) or Training as Usual (TAU; n = 92) which provided trainings per agency routine. Practitioners completed self-report measures at four time points (0, 6, 12, and 18 months following baseline). Of those assigned to AF-CBT, 89% participated in at least one training activity and 68% met a “training completion” definition. A total of 80 (44%) practitioners were still active clinicians in the study by 18-month assessment in that they had not met our staff turnover or study withdrawal criteria. Using an intent-to-train design, hierarchical linear modeling analyses revealed significantly greater initial improvements for those in the AF-CBT training condition (vs. TAU condition) in CBT-related knowledge and use of AF-CBT teaching processes, abuse-specific skills, and general psychological skills. In addition, practitioners in both groups reported significantly more negative perceptions of organizational climate through the intervention phase. These significant, albeit modest, findings are discussed in the context of treatment training, research, and work force issues as they relate to the diverse backgrounds, settings, and populations served by community practitioners.

PURPOSE We studied the effect of 3 antidepressant treatments on outcomes (depressive severity, medication tolerability, and psychosocial functioning) in depressed patients having comorbid general medical conditions in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. METHODS Adult outpatients who had chronic and/or recurrent major depressive disorder (MDD) with and without general medical conditions were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram plus placebo, (2) bupropion-SR plus escitalopram, or (3) venlafaxine-XR plus mirtazapine. At weeks 12 and 28, we compared response and tolerability between participants with 0, 1, 2, and 3 or more general medical conditions. RESULTS Of the 665 evaluable patients, 49.5% reported having no treated general medical conditions, 23.8% reported having 1, 14.8% reported having 2, and 11.9% reported having at least 3. We found only minimal differences in antidepressant treatment response between these groups having different numbers of conditions; patients with 3 or more conditions reported higher rates of impairment in social and occupational functioning at week 12 but not at week 28. Additionally, we found no significant differences between the 3 antidepressant treatments across these groups. CONCLUSIONS Patients with general medical conditions can be safely and effectively treated for MDD with antidepressants with no additional adverse effect or tolerability burden relative to their counterparts without such conditions. Combination therapy is not associated with an increased treatment response beyond that found with traditional monotherapy in patients with MDD, regardless of the presence and number of general medical conditions.

The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.Baseline and course features of individuals with suicide events are described.Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt.While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder.Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.

Background Impairment-based exercise programs have yielded only small to moderate benefits in reducing pain and improving function in people with knee osteoarthritis (OA). It has previously been proposed that adding agility and perturbation training to exercise programs for people with knee OA may improve treatment effects for pain and function. Objective The purpose of this study was to examine the effectiveness of adding agility and perturbation techniques to standard exercise therapy compared with the standard exercise program alone for people with knee OA. Design This was a single-blinded randomized controlled trial. Setting The study was conducted in the outpatient physical therapy clinic of a large, university-based health center. Participants One hundred eighty-three people with knee OA (122 women, 61 men) participated. Interventions Participants were randomly assigned to either a group that received agility and perturbation training with standard exercise therapy or a group that received only the standard exercise program. Measurements The outcome measures were self-reported knee pain and function, self-reported knee instability, a performance-based measure of function, and global rating of change. Results Although both groups exhibited improvement in self-reported function and in the global rating of change at the 2-, 6-, and 12-month follow-up periods, there were no differences between groups on these outcomes. There was no reduction in knee pain or improvement in performance-based function in either group. Limitations It is possible that more-intense application of the interventions or application of the interventions to participants with knee OA who were at greater risk for falling may have yielded additive effects of the agility and perturbation training approach. Conclusions Both intervention groups exhibited improvement in self-reported function and the global rating of change. Our results, however, did not support an additive effect of agility and perturbation training with standard exercise therapy in our sample of individuals with knee OA. Further study is needed to determine whether there are subgroups of individuals who might achieve an added benefit with this approach.

Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI).Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d], paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2.Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with nonremission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy.

Introduction: Insomnia symptoms, which are common in depression, have a significant impact on function and quality of life. However, little is known about the prevalence and associated features of insomnia symptoms in representative treatment-seeking patients with depression. Methods: Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. STAR*D recruited 3,743 adult outpatients diagnosed with nonpsychotic major depressive disorder (MDD) from primary (n=18) and psychiatric care (n=23) clinics across the United States. Baseline sociodemographic and clinical features were compared between those with insomnia symptoms (84.7%) and those without (15.3%). Results: The most common presentation was the simultaneous presence of sleep onset, mid-nocturnal, and early morning insomnia symptoms (27.1%). Of these three types of insomnia symptoms, mid-nocturnal insomnia symptoms were the most commonly found alone (13.5%) and in combination with one or more other types (82.3%). Insomnia symptoms were associated with several indicators of a more severe depressive illness. Only a small proportion of participants with insomnia symptoms were receiving treatment for sleep disturbances at study initiation, and the vast majority of those receiving treatment still reported having insomnia symptoms. Conclusion: In outpatients who seek treatment for nonpsychotic MDD in typical clinical settings, insomnia symptoms are very common, undertreated, and indicative of a more severe depression.

α-Synuclein is one of the most abundant proteins in presynaptic terminals. Normal expression of α-synuclein is essential for neuronal survival and it prevents the initiation of apoptosis in neurons through covalent cross-linking of cytochrome c released from mitochondria. Exocytosis of α-synuclein occurs with neuronal mitochondrial dysfunction, making its detection in cerebrospinal fluid (CSF) of children after severe traumatic brain injury (TBI) a potentially important marker of injury. Experimental therapeutic hypothermia (TH) improves mitochondrial function and attenuates cell death, and therefore may also affect CSF α-synuclein concentrations. We assessed α-synuclein levels in CSF of 47 infants and children with severe TBI using a commercial ELISA for detection of monomeric protein. 23 patients were randomized to TH based on published protocols where cooling (32–33°C) was initiated within 6–24 h, maintained for 48 h, and then followed by slow rewarming. CSF samples were obtained continuously via an intraventricular catheter for 6 days after TBI. Control CSF (n = 9) was sampled from children receiving lumbar puncture for CSF analysis of infection that was proven negative. Associations of initial Glasgow Coma Scale (GCS) score, age, gender, treatment, mechanism of injury and Glasgow Outcome Scale (GOS) score with CSF α-synuclein were compared by multivariate regression analysis. CSF α-synuclein levels were elevated in TBI patients compared to controls (p = 0.0093), with a temporal profile showing an early, approximately 5-fold increase on days 1–3 followed by a delayed, >10-fold increase on days 4–6 versus control. α-Synuclein levels were higher in patients treated with normothermia versus hypothermia (p = 0.0033), in patients aged

Background Individuals with diabetes mellitus (DM) are two to four times more likely to be diagnosed with major depressive disorder (MDD). However, few controlled studies have examined the impact of DM on the treatment of MDD. Understanding the effect of DM on depressed patients could provide valuable clinical information toward adjusting current treatment modalities to produce a more effective treatment for depressed patients with DM. Methods This study was conducted using an evaluable sample of 2876 outpatient participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Sociodemographic and clinical characteristics and treatment characteristics with the selective serotonin reuptake inhibitor (SSRI) citalopram, as well as remission rates for MDD and time to remission, were compared between participants with DM and participants without DM. Results The odds of remission were lower in participants with DM than in those without DM prior to adjustment [odds ratio (OR)=0.68; 95% confidence interval (95% CI)=(0.49, 0.94); P=.0184]. These differences were no longer present after adjustment [OR=0.92; 95% CI=(0.64, 1.32); P=.6399]. Participants with DM reported fewer side effects than participants without DM despite similar dosing. Conclusions Depressed patients with DM and depressed patients without DM appear to have similar rates of MDD remission, indicating that a diagnosis of DM per se has no impact on MDD remission. The findings of fewer side effects and psychiatric serious adverse events in participants with DM imply that depressed patients with DM may be excellent candidates for more aggressive SSRI dosing. This lower prevalence of side effects reported by depressed participants with DM warrants further exploration.

Traumatic brain injury (TBI) is the most common cause of death for children less than 18 years of age. Current standards of care for children with severe TBI include monitoring of intracranial pressure (ICP), and goal-directed therapies to minimize ICP and optimize cerebral perfusion pressure (CPP; the mathematical difference between the mean arterial pressure and ICP). Current guidelines for ICP and CPP thresholds suggest that age-based thresholds should be adopted, but few studies have included the youngest children affected by TBI (those 15 or >20 mm Hg; CPP 20 mm Hg between the outcome groups [median (25–75%): favorable 0 (0–1) vs. unfavorable 1 (0–4); p = 0.17]. To our knowledge, this is the first exploratory report to test if CPP and ICP thresholds can be established for this young population of children after TBI, and it suggests a CPP target threshold of 45 mm Hg. Despite good ICP control in this population, there was still a 50% incidence of unfavorable outcome, suggesting that there may be unique physiologic parameters that need to be targeted in infants with severe TBI. A prospective study is needed to fully determine what goals should be targeted for this vulnerable population.

Introduction: This article presents baseline findings that describe how nonclinical factors were associated with patient use of psychiatric and general medical care and how those relationships changed after patients enrolled in the 41‐site Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). Aims: STAR*D offered adult outpatients with major depression diligently delivered, measurement‐based care. To achieve full remission within a tolerable medication dose, recommendations for treatment based on routine symptom and side‐effect measurements were discussed with patients by clinical research coordinators and offered to clinicians who could flexibly tailor that guidance to accommodate individual patient needs. Medications were provided gratis. Pre‐ and post‐enrollment data came from provider records and from patient face‐to‐face, telephone, and computer‐assisted surveys. Two‐part nested mixed models assessed patient likelihood and volume of mental and general medical care services. Results: Prior to enrollment, predisposing (gender, race, education, and care attitude), affordability (private insurance), and clinical factors (depressive symptoms and mental and physical functioning) were found to be important drivers of patient use of psychiatric and general medical care. After STAR*D enrollment, however, predisposing factors were less important drivers of psychiatric service use but remained important drivers of general medical care. Conclusions: Data suggest diligent, measurement‐based mental health programs may reduce race, gender, and education disparities in the use of needed mental health care.

The authors provide an overview of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org), a large-scale practical clinical trial to determine which of several treatments are the most effective "next-steps" for patients with major depressive disorder whose symptoms do not remit or who cannot tolerate an initial treatment and, if needed, ensuing treatments. Entry criteria were broadly defined and inclusive, and patients were enrolled from psychiatric and primary care clinics. All participants began on citalopram and were managed by clinic physicians, who followed an algorithm-guided acute-phase treatment through five visits over 12 weeks. At the end of each sequence, patients whose depression had not fully remitted were eligible for subsequent randomized trials in a sequence of up to three clinical trials. In general, remission rates in the study clinics were lower than expected, suggesting the need for several steps to achieve remission for most patients. There was no clear medication "winner" for patients whose depression did not remit after one or more aggressive medication trials. Both switching and augmenting appeared to be reasonable options when an initial antidepressant treatment failed, although these two strategies could not be directly compared. Further, the likelihood of remission after two vigorous medication trials substantially decreased, and remission would likely require more complicated medication regimens for which the existing evidence base is quite thin. STAR*D demonstrated that inclusion of more real-world patients in clinical trials is both feasible and informative. Policy implications of the findings, as well as the study's limitations, are discussed.